This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Early ovarian failure and infertility are well-known side effects of anti-cancer treatments. The long-term consequences of these treatments on non-target tissues, such as the ovaries are substantial. Attempts to preserve fertility and ovarian function in female cancer patients have met with little success. In mice, sphingosine-1-phosphate (S1P), a metabolite of the pro-apoptotic stress sensor ceramide, completely protects the ovaries from radiation-induced damage in vivo. In vivo, S1P preserves a normal level of fertility in irradiated female mice, and offspring conceived with oocytes protected from radiation by S1P show no evidence of transgenerational genomic damage. Thus, S1P-based strategies could be developed to combat infertility and ovarian failure. The safety and efficacy of S1P for preserving ovarian function and fertility in primates exposed to anti-cancer treatments needs to be established. Technologies to deliver S1P only to the ovaries, thereby preventing systemic availability of S1P that could benefit the tumor cells targeted for destruction, also requires validation. The specific aims are 1) to determine if S1P can be administered directly into the rhesus monkey ovary to protect the gonads from radiotherapy-induced damage in vivo;2) to evaluate the competency of macaque oocytes protected from radiotherapy by S1P for fertilization and embryogenesis;and 3) to assess if offspring conceived from macaque oocytes protected from radiotherapy by S1P in vivo show evidence of propagated genomic damage. The long-term goal is to develop safe and effective strategies for protecting human ovaries in vivo from the side-effect damage caused by anti-cancer therapies, and prevent infertility.